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Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA)

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Abstract

Background

Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients.

Patients and methods

The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM® program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses.

Results

A total of 91 patients with malignant lymphoma [non-Hodgkin’s lymphoma (NHL): 79; Hodgkin’s lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS.

Conclusion

This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment.

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References

  1. Argiris A, Seropian S, Cooper DL (2000) High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin’s disease. Ann Oncol 11:665–672

    Article  CAS  PubMed  Google Scholar 

  2. Beal SL, Sheiner LB, Boeckmann A, Bauer RJ (2009) NONMEM User’s Guides (1989–2009). Icon, Ellicott City

    Google Scholar 

  3. Brendel K, Comets E, Laffont C, Laveille C, Mentre F (2006) Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23:2036–2049

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244

    CAS  PubMed  Google Scholar 

  5. Ciccolini J, Monjanel-Mouterde S, Bun SS, Blanc C, Duffaud F, Favre R, Durand A (2002) Population pharmacokinetics of etoposide: application to therapeutic drug monitoring. Ther Drug Monit 24:709–714

    Article  CAS  PubMed  Google Scholar 

  6. Clark PI, Slevin ML, Joel SP, Osborne RJ, Talbot DI, Johnson PW, Reznek R, Masud T, Gregory W, Wrigley PF (1994) A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity. J Clin Oncol 12:1427–1435

    CAS  PubMed  Google Scholar 

  7. Corradini P, Vitolo U, Rambaldi A, Miceli R, Patriarca F, Gallamini A, Olivieri A, Benedetti F, Todeschini G, Rossi G, Salvi F, Bruno B, Baldini L, Ferreri A, Patti C, Tarella C, Pileri S, Dodero A (2014) Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma. Leukemia 28(9):1885–1891

    Article  CAS  PubMed  Google Scholar 

  8. Dartois C, Brendel K, Comets E, Laffont CM, Laveille C, Tranchand B, Mentre F, Lemenuel-Diot A, Girard P (2007) Overview of model-building strategies in population PK/PD analyses: 2002–2004 literature survey 1. Br J Clin Pharmacol 64:603–612

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dorken B, Muller-Hermelink HK, Duhmke E, Loeffler M (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 348:2386–2395

    Article  CAS  PubMed  Google Scholar 

  10. Ette EI, Williams PJ, Kim YH, Lane JR, Liu MJ, Capparelli EV (2003) Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol 43:610–623

    Article  CAS  PubMed  Google Scholar 

  11. Fitoussi O, Belhadj K, Mounier N, Parrens M, Tilly H, Salles G, Feugier P, Ferme C, Ysebaert L, Gabarre J, Herbrecht R, Janvier M, Van Den Neste E, Morschhauser F, Casasnovas O, Ghesquieres H, Anglaret B, Brechignac S, Haioun C, Gisselbrecht C (2011) Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA. Haematologica 96:1136–1143

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Gisselbrecht C (2012) Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Hematol Am Soc Hematol Educ Program 2012:410–416

    Google Scholar 

  13. Greco FA (1999) Oral etoposide in lymphoma. Drugs 58(Suppl 3):35–41

    Article  CAS  PubMed  Google Scholar 

  14. Gurney H (1996) Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol 14:2590–2611

    CAS  PubMed  Google Scholar 

  15. Josting A, Muller H, Borchmann P, Baars JW, Metzner B, Dohner H, Aurer I, Smardova L, Fischer T, Niederwieser D, Schafer-Eckart K, Schmitz N, Sureda A, Glossmann J, Diehl V, DeJong D, Hansmann ML, Raemaekers J, Engert A (2010) Dose intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol 28:5074–5080

    Article  PubMed  Google Scholar 

  16. Kaestner SA, Sewell GJ (2007) Chemotherapy dosing part I: scientific basis for current practice and use of body surface area. Clin Oncol (R Coll Radiol) 19:23–37

    Article  CAS  Google Scholar 

  17. Karlsson MO, Savic RM (2007) Diagnosing model diagnostics. Clin Pharmacol Ther 82:17–20

    Article  CAS  PubMed  Google Scholar 

  18. Milpied N (2014) The role of myeloablation for lymphoma. N Engl J Med 370:576

    PubMed  Google Scholar 

  19. Montecucco A, Biamonti G (2007) Cellular response to etoposide treatment. Cancer Lett 252:9–18

    Article  CAS  PubMed  Google Scholar 

  20. Mounier N, Gisselbrecht C (1998) Conditioning regimens before transplantation in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 9(Suppl 1):S15–S21

    Article  PubMed  Google Scholar 

  21. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–1545

    Article  CAS  PubMed  Google Scholar 

  22. Rancea M, Skoetz N, Monsef I, Hubel K, Engert A, Bauer K (2012) Fourteenth biannual report of the Cochrane Haematological Malignancies Group—focus on autologous stem cell transplantation in hematological malignancies. J Natl Cancer Inst 104:NP

  23. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Muller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 359:2065–2071

    Article  CAS  PubMed  Google Scholar 

  24. Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI (2013) Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681–1690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Tranchand B, Amsellem C, Chatelut E, Freyer G, Iliadis A, Ligneau B, Trillet-Lenoir V, Canal P, Lochon I, Ardiet CJ (1999) A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients. Cancer Chemother Pharmacol 43:316–322

    Article  CAS  PubMed  Google Scholar 

  26. van den Bongard HJ, Mathot RA, Beijnen JH, Schellens JH (2000) Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet 39:345–367

    Article  PubMed  Google Scholar 

  27. Wilde S, Jetter A, Rietbrock S, Kasel D, Engert A, Josting A, Klimm B, Hempel G, Reif S, Jaehde U, Merkel U, Busse D, Schwab M, Diehl V, Fuhr U (2007) Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin’s lymphoma and its effect on myelotoxicity. Clin Pharmacokinet 46:319–333

    Article  CAS  PubMed  Google Scholar 

  28. You B, Tranchand B, Girard P, Falandry C, Ribba B, Chabaud S, Souquet PJ, Court-Fortune I, Trillet-Lenoir V, Fournel C, Tod M, Freyer G (2008) Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study. Lung Cancer 62:261–272

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors want to thank the study coordinators who enrolled the patients.

Funding

The study was supported by a French Programme Hospitalier de Recherche Clinique (PHRC) obtained in 2001.

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Authors and Affiliations

  1. EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France

    Benoit You, Emilie Hénin, Jéome Guitton, Michel Tod & Gilles Freyer

  2. Service d’Oncologie Médicale, Centre d’Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France

    Benoit You, Emilie Hénin, Jéome Guitton, Michel Tod & Gilles Freyer

  3. Service d’hématologie, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Centre Hospitalier Lyon-Sud, Pierre-Benite, France

    Gilles Salles & Emmanuel Bachy

  4. Université Lyon 1, Lyon, France

    Gilles Salles & Emmanuel Bachy

  5. Service d’hématologie, Centre d’Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Centre Hospitalier Universitaire de Dijon, 21034, Dijon, France

    Olivier Casasnovas

  6. Centre Henri Becquerel, 76038, Rouen, France

    Hervé Tilly

  7. Institut Gustave Roussy, 94805, Villejuif, France

    Vincent Ribrag

  8. Centre Léon Bérard, 69008, Lyon, France

    Catherine Sebban

Authors
  1. Benoit You
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  2. Gilles Salles
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  3. Emmanuel Bachy
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  4. Olivier Casasnovas
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Correspondence to Benoit You.

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You, B., Salles, G., Bachy, E. et al. Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA). Cancer Chemother Pharmacol 76, 939–948 (2015). https://doi.org/10.1007/s00280-015-2866-9

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  • DOI: https://doi.org/10.1007/s00280-015-2866-9

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